1. Field of the Invention
The present invention relates to a method to prepare microcapsules, microspheres, nanocapsules and nanospheres. More particularly, the present invention relates to an emulsion-based method for preparing microcapsules or microspheres containing water-soluble or oil-soluble agents, particularly highly water-soluble agents.
2. Description of the Prior Art
Microcapsules and microspheres are usually powders consisting of spherical particles 2 millimeters or less in diameter, usually 500 microns or less in diameter. If the particles are less than 1 micron, they are often referred to as nanocapsules or nanospheres. For the most part, the difference between microcapsules and nanocapsules is their size; their internal structure is about the same. Similarly, the difference between microspheres and nanospheres is their size; their internal structure is about the same.
A microcapsule (or nanocapsule) has its encapsulated material, herein after referred to as agent, centrally located within a unique membrane, usually a polymeric membrane. This membrane may be termed a wall-forming material, and is usually a polymeric material. Because of their internal structure, permeable microcapsules designed for controlled-release applications release their agent at a constant rate (zero-order rate of release). Also, impermeable microcapsules can be used for rupture-release applications. Hereinafter, the term microcapsule will include nanocapsules, microbubbles (hollow particles), porous microbubbles and particles in general that comprise a central core surrounded by a unique outer membrane.
A microsphere has its agent dispersed throughout the particle; that is, the internal structure is a matrix of the agent and excipient, usually a polymeric excipient. Usually controlled-release microspheres release their agent at a declining rate (first-order). But microspheres can be designed to release agents at a near zero-order rate. Microspheres tend to be more difficult to rupture as compared to microcapsules because their internal structure is stronger. Hereinafter, the term microsphere will include nanospheres, microparticles, nanoparticles, microsponges (porous microspheres) and particles in general, with an internal structure comprising a matrix of agent and excipient.
A wide variety of methods to prepare microcapsules and microspheres are described in the literature. Several of these methods make use of emulsions to make microspheres, in particular to make microspheres less than 2 millimeters in diameter. To give a general example of such processes, one can dissolve a polymer in a suitable organic solvent (the polymer solvent), dissolve or disperse an agent in this polymer solution, disperse the resulting polymer/agent mixture into an aqueous phase (the processing medium) to obtain an oil-in-water emulsion with oil microdroplets dispersed in the processing medium, and remove the solvent from the microdroplets to form microspheres. These processes can also be performed with water-in-oil emulsions and with double emulsions.
The use of emulsion-based processes that follow this basic approach is described in several U.S. patents. For example, U.S. Pat. No. 4,384,975 describes the production of microspheres by forming an emulsion and then slowly removing the polymer solvent from the microdroplets in the emulsion by vacuum distillation. As another example, U.S. Pat. No. 3,891,570 discloses a method in which the polymer solvent is removed from the microdroplets in the emulsion by applying heat or reducing the pressure in the fabrication vessel. In still another example, U.S. Pat. No. 4,389,330, the polymer solvent is partially removed from the microdroplets in the emulsion by vacuum distillation (preferably 40 to 60% of the polymer solvent) and then the remainder of the polymer solvent is extracted to solidify the microspheres.
The disadvantage of the above-described processes, as with other emulsion-based processes, is that certain agents can partition into the processing medium, that is, the agents migrate out of the microdroplets during the polymer solvent removal step, resulting in a poor encapsulation efficiency. Furthermore, all of the above-described processes afford microspheres rather than microcapsules.
Another emulsion-based method to prepare microspheres described in U.S. Pat. No. 3,737,337 uses a controlled extraction of the polymer solvent from the microdroplets by adding processing medium to the emulsion at a controlled rate. However, this patent teaches away from the present invention by disclosing that the extraction must proceed slowly or no spherical particles will be formed. Similarly, U.S. Pat. No. 4,652,441 describes a method to encapsulate water-soluble agents from water-in-oil-in-water emulsions, and teaches that a high-viscosity, drug-retaining substance must be included in the inner water phase to retain the drug in the microdroplets during evaporation of the polymer solvent. U.S. Pat. No. 4,652,441 also teaches against the present invention by suggesting that it is impossible to effectively encapsulate water-soluble agents without using drug-retaining substances in the emulsion.